Abstract ND08: Discovery of FX-909, a first-in-class inverse agonist of the peroxisome proliferator-activated receptor gamma (PPARG) lineage transcription factor, to potentially treat patients with the luminal subtype of advanced urothelial cancer (UC)
Authors: Robert Sims, Jennifer A. Mertz, Jonathan E. Wilson, James E. Audia, Kaylyn E. Williamson, Yong Li, Miljan Kuljanin, Will W. Motely, Byron DeLaBarre, Michaela Bowden, Jacob I. Stuckey
Journal: Cancer Research (2023)

Abstract Although the treatment landscape of advanced urothelial cancer (UC) has changed dynamically over the last decade, metastatic UC still has amongst the worst 5-year recurrence rate of any cancer type, highlighting the need for new therapeutic options for these patients. Analogous to breast cancer, advanced UC is a heterogeneous disease, with luminal and basal subtypes. For luminal breast cancer, small molecule targeting of the lineage-defining transcription factor estrogen receptor (ER) is a demonstrated and effective therapeutic strategy. Two-thirds of advanced UC is classified as luminal, which is characterized by overexpression of the urothelial lineage-defining transcription factor PPARG. Thus, small molecule targeting of PPARG in luminal UC may serve as a therapeutic strategy analogous to ER in luminal breast cancer. While PPARG agonists have been well studied in the context of metabolic disease, PPARG inhibitors have received far less attention. Previously reported PPARG inhibitors display minimal phenotypic activity in pre-clinical UC models, calling into question the performance of these molecules, or alternatively, the role of PPARG as a survival lineage oncogene in UC. Leveraging reconstituted, multi-component PPARG biochemical systems, we first identified the limitations of previous tool compounds and then discovered a novel, covalent lead series with unique, context-dependent electrophilic properties. These efforts lead to the discovery of FX-909, a first-in-class covalent PPARG inverse agonist with powerful repressive conformational biasing activity. FX-909 is highly potent in cells (IC50=1 nM), demonstrates high specificity for PPARG (&amp;gt;2000-fold selective over PPARA/PPARD), and elicits robust in vitro growth inhibition in UC cell lines with activated PPARG signaling. Tumor regression was observed in UMUC9 (PPARG amplification) and HT1197 (RXRAS427F hotspot mutation) xenograft models of UC with oral dosing at 1 mg/kg. Predictable, on-target and reversible pharmacology was observed at FX-909 doses above 1 mg/kg, mimicking PPARG loss-of-function mutations with notable tissue remodeling in adipose tissue and the normal urothelium. These collective findings corroborate the role of PPARG as a key UC survival oncogene and suggest that FX-909 will be an effective therapy for patients with advanced UC harboring the luminal subtype. Citation Format: Robert Sims, Jennifer A. Mertz, Jonathan E. Wilson, James E. Audia, Kaylyn E. Williamson, Yong Li, Miljan Kuljanin, Will W. Motely, Byron DeLaBarre, Michaela Bowden, Jacob I. Stuckey. Discovery of FX-909, a first-in-class inverse agonist of the peroxisome proliferator-activated receptor gamma (PPARG) lineage transcription factor, to potentially treat patients with the luminal subtype of advanced urothelial cancer (UC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr ND08.